Abstract
Abstract Autoimmune diseases are driven, in large part, by the aberrant activation of lymphocytes which mediate a dysregulated cytokine milieu and produce pathogenic, auto-reactive antibodies. Notably, many cytokines, including interferon gamma (IFN-γ), utilize the JAK/STAT pathway for signal propagation. Suppressor of Cytokine Signaling-1 (SOCS-1) is an inducible, intracellular protein known to regulate IFN-γ signaling through dampening of the JAK/STAT signaling cascade. We have previously shown that a peptide mimicking the kinase inhibitory region of SOCS1 (SOCS1-KIR) inhibited IFN-γ signaling and inflammation-driven disease progression. Using Fas deficient MRL/lpr mice, which spontaneously develop a lupus-like disease, we tested the hypothesis that SOCS1-KIR administration would alter lymphocyte phenotype and modulate lupus-associated pathologies. SOCS1-KIR administration reduced severity of skin lesions, autoantibody production, and modestly reduced kidney pathology. On a cellular level, peritoneal SOCS1-KIR administration enhanced Foxp3 expression in total splenic and follicular regulatory T cells, reduced the effector memory/naïve T lymphocyte ratio for both CD4+ and CD8+ cells, and reduced the frequency of germinal center B cells. Together, these data show that SOCS1-KIR treatment altered lymphocyte phenotype and suggest that therapeutic targeting of the SOCS1 pathway through peptide administration may have efficacy in mitigating autoimmune pathologies.
Published Version
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